Mast cells adhere to fibronectin following activation with the mast cell growth factor c-kit ligand (also known as stem cell factor), but not after addition of IL-3. This process is integrin-mediated and follows the specific interaction between c-kit ligand and c-kit ligand-induced mast cell adhesion. Because c-kit is produced by resident connective tissue cells, it is a strong candidate for the physiologic stimulus responsible for the specific tissue localization of mast cells. Mast cells exhibit spontaneous adhesion to vitronectin. The engagement of mast cells to vitronectin through a vitronectin receptor is followed by an increase in proliferative rate and the rapid phosphorylation of at lease one protein. IL-3 dependent mast cells undergo apoptosis (programmed cell death) following removal of IL-3. This is prevented by the addition of c-kit ligand, and this effect is not prevented by dexamethasone or cyclosporin. W/WV mast cells with defective c-kit undergo IL-3 deprivation-induced apoptosis despite the addition of c-kit ligand. c-Kit ligand in vitro induces mast cell maturation toward the connective tissue mast cell phenotype. Mouse bone marrow-derived mast cells respond to both IL-3 and c-kit ligand and are inhibited by m-CSF, GM-CSF, gamma- IFN, and NGF. Mouse peripheral blood mononuclear cell-derived mast cells respond only to c-kit ligand. Human peripheral blood-derived human mast cells are derived from a CD34+ cell population. CD34 positivity is rapidly lost in culture, while the cell population becomes FcERI+.